Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a poor prognosis. Diagnosis and treatment of this tumor remains challenging. The Weiss score, the current gold standard for the histopathological diagnosis of ACC, lacks diagnostic accuracy of borderline tumors (Weiss score 2 or 3) and is subject to inter observer variability. Furthermore, adjuvant and palliative systemic therapy have limited effect and no proven overall survival benefit. A better insight in the molecular background of ACC might identify markers that improve diagnostic accuracy, predict treatment response or even provide novel therapeutic targets. This systematic review of the literature aims to provide an overview of alterations in DNA methylation, histone modifications and their potential clinical relevance in ACC. (C) 2017 Elsevier B.V. All rights reserved.